AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice

• Published in: The Journal of neuroscience 2013-06, Vol.33 (24), p.10075-10084
• Main Authors: Eketjäll, Susanna, Janson, Juliette, Jeppsson, Fredrik, Svanhagen, Alexander, Kolmodin, Karin, Gustavsson, Susanne, Radesäter, Ann-Cathrin, Eliason, Kristina, Briem, Sveinn, Appelkvist, Paulina, Niva, Camilla, Berg, Anna-Lena, Karlström, Sofia, Swahn, Britt-Marie, Fälting, Johanna
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; Cells, Cultured; Cerebral Cortex - pathology; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Guinea Pigs; Humans; Isoindoles - pharmacology; Isoindoles - therapeutic use; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Neurochemistry with Molecular Neurobiology; neurokemi med molekylär neurobiologi; Neurons - drug effects; Neurons - metabolism; Peptide Fragments - metabolism; Pyridones - pharmacology; Pyridones - therapeutic use; Time Factors
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.1165-13.2013

Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aβ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.